Chapter 21 Abnormal Uterine Bleeding
BACKGROUND AND DEFINITIONS
Abnormal uterine bleeding (AUB) is among the most common diagnostic and therapeutic challenges faced by gynecologists. Complaints of AUB account for more than a third of gynecology visits.1 An indication of how difficult this problem can be to treat is that AUB remains the indication for half the hysterectomies performed in the United States. The inability to find any pathologic abnormality in 20% of these hysterectomy specimens suggests that AUB is often caused by potentially treatable hormonal or systemic conditions.2
Definition
Abnormal uterine bleeding is an all-inclusive term used to describe any uterine bleeding outside the parameters of normal menstruation that occurs during the reproductive years. It does not include bleeding that originates lower in the genital tract (i.e., the vagina or vulva). It usually does include bleeding originating from either the uterine fundus or cervix, because these causes are difficult to distinguish clinically, and should both be considered in all patients presenting with bleeding from the uterus. Abnormal bleeding can occur during childhood or after the menopause. However, because the differential diagnoses and thus the diagnostic approach are markedly different during these time periods, bleeding in these age groups is considered separately in Chapters 13 and 24.
Normal Menstruation
Exactly what is considered normal menstruation is somewhat subjective and often varies between individual women and certainly between cultures. However, normal menstruation (eumenorrhea) can be defined as bleeding that occurs after ovulatory cycles every 21 to 35 days, lasts 3 to 7 days, and is not excessive. The total amount of blood lost during a normal menstrual period has been found to be no more than 80mL, although this is difficult to estimate clinically, because much of the menstrual effluent is dissolved endometrium.3 Normal menses do not cause severe pain, do not include passage of identifiable clots, and do not require the patient to change pads or tampons more than once per hour. It follows that AUB is any bleeding that falls outside these parameters.
Abnormal Uterine Bleeding Terminology
The following descriptive terms are often used to describe AUB:
Dysfunctional Uterine Bleeding: An Obsolete Diagnostic Term
Dysfunctional uterine bleeding is a traditional term that was used for years to refer to excessive uterine bleeding in cases where no uterine pathology could be identified.4 However, the development of a greater understanding of AUB and the continuing development of more sophisticated diagnostic techniques has made this term outdated.
Clinically, treatment will always be the most effective when specific causes of AUB can be identified. Because grouping widely divergent causes of AUB together in a poorly defined group is unlikely to improve diagnosis or treatment, a national consensus group has recently concluded that dysfunctional uterine bleeding no longer has any usefulness in clinical medicine.5
ABNORMAL UTERINE BLEEDING CAUSED BY UTERINE CONDITIONS
Different causes of AUB can be grouped according to their basic pathophysiology (Tables 21-1 and 21-2). The clinician must keep in mind that any individual patient can simultaneously have two or more causes of uterine bleeding. For this reason, the workup must evaluate patients simultaneously for the most likely and most serious anatomic and systemic etiologies based on clinical presentation.
Table 21-1 Common Uterine Conditions Associated with Abnormal Uterine Bleeding
Table 21-2 Incidence of Endometrial Polyps and the Risk of Associated Malignancies as a Function of Age.
| Age Group (Years of age) | Incidence of Endometrial Polyps | Risk of Associated Malignancy |
|---|---|---|
| 25–35 | 9% | 2% |
| 36–45 | 27% | 11% |
| 46–55 | 29% | 15% |
| 56–65 | 18% | 17% |
| >65 | 17% | 55% |
Data from Hileeto D, Fadare O, Martel M, Zheng W: Age-dependent association of endometrial polyps with increased risk of cancer involvement. World J Surg Oncol 3:8, 2005.
Pregnancy
Normal pregnancies, spontaneous abortions, and ectopic pregnancies together represent the most common causes of AUB in the reproductive-age group. First-trimester bleeding occurs in up to 25% of all pregnancies and is associated with an increased risk of several common complications.6 In approximately half of these cases, bleeding will be an early symptom of impending spontaneous abortion, whereas the remaining half will ultimately prove to have a viable pregnancy. Ectopic pregnancies, which currently make up 2% of all pregnancies, will commonly present with AUB as one of the symptoms as well.7 Gestational trophoblastic disease is another pregnancy-related problem that presents as AUB in more than 80% of cases.8 Pregnancy must be ruled out in every case of AUB in reproductive-age women, no matter how obvious any alternative causal diagnoses might be.
Uterine Pathology
An important and expected priority for gynecologists is to precisely identify uterine pathology that might contribute to uterine bleeding (see Table 21-1). Most of these diagnoses can be determined to be related to infection and neoplasm. An additional common uterine pathology related to AUB is adenomyosis.
Infection
Infection is a surprisingly common cause of AUB and is often the basis of what appears to be AUB. In obvious cases of pelvic inflammatory disease (see Chapter 33), approximately 40% of the patients will present with vaginal bleeding.9 An underrecognized cause of uterine bleeding is endometritis. Although chronic endometritis was classically diagnosed only when plasma cells were found on endometrial biopsy, recent studies have found an association between AUB and reactive changes in the surface endometrium, but no association with the presence of a particular type of inflammatory cell.10 Other studies have verified that subclinical endometritis is a common finding in patients diagnosed with AUB and can be related to any of a number of pathogens.11
Cervicitis is another common cause of AUB characterized by postcoital spotting. In addition to common sexually transmitted diseases (i.e., chlamydia and gonorrhea), other vaginal flora and pathogens can be involved.12 Postcoital bleeding is the most common presenting symptom in women found to have chlamydia infections.13
Neoplasms
AUB can be a marker for gynecologic neoplasms. These neoplasms can be benign (e.g., leiomyoma, endometrial or endocervical polyps) or malignant (e.g., endometrial or cervical carcinoma). Focal intracavitary lesions account for up to 40% of cases of AUB.14 Ovarian neoplasms can indirectly cause irregular bleeding by interfering with ovulation Some of the most common neoplasms known to cause AUB are reviewed here.
Leiomyomas
These benign myometrial tumors are remarkably common and by age 50 can be found in nearly 70% of white women and more than 80% of black women on ultrasonographic examination.15 However, many of these leiomyomas are subclinical, and estimates of symptomatic leiomyomas range from 20% to 40%.
Endometrial Polyps
Endometrial polyps are localized overgrowths of the endometrium that project into the uterine cavity. Such polyps may be broad-based (sessile) or pedunculated. Endometrial polyps are surprisingly common in both premenopausal and postmenopausal women, and are found in at least 20% of women undergoing hysteroscopy or hysterectomy.16 The incidence of these polyps rises steadily with increasing age, peaks in the fifth decade of life, and gradually declines after menopause.
Studies have found that from 5% to 33% of premenopausal women complaining of AUB will be found to have endometrial polyps.17,18 Endometrial polyps are commonly found in patients with a long history of anovulatory bleeding, suggesting that polyps might be the result of chronic anovulation in some women. Polyps are also found in women complaining of postmenstrual spotting or bleeding in ovulatory cycles or during cyclic hormonal therapy.
Although endometrial polyps in premenopausal women are usually benign, the risk of associated endometrial malignancy increases significantly with age, such that in women older than age 65 the risk of malignancy is greater than 50% (see Table 21-2).16 In one pathologic study of 513 women with endometrial polyps, associated carcinomas were endometrioid in 58, serous in 6, carcinosarcoma in 1, and clear cell in 1.16
Endometrial Cancer
The single most important disease to identify early in the evaluation of a perimenopausal or postmenopausal woman is endometrial cancer. In women age 40 to 49, the incidence of endometrial carcinoma is 36 per 100,000.19 After the menopause, approximately 10% of women with AUB will be found to have endometrial cancer, and the incidence increases with each decade of life thereafter.
Endocervical Polyps
The cause of endocervical polyps is unclear, but they are known to be more frequent in women on oral contraceptives or with chronic cervicitis. Microscopically, endocervical polyps consist of a vascular core surrounded by a glandular mucous membrane and may be covered completely or partially with stratified squamous epithelium. In some cases, the connective tissue core may be relatively fibrous. Endocervical polyps removed from women taking oral contraceptives often show a pattern of microglandular hyperplasia.20
Cervical Cancer
As many as 17% of women presenting with postcoital spotting will be found to have cervical dysplasia; 4% will have invasive cancer.21 In the absence of a visible lesion, Papanicolaou smears and colposcopy (if indicated) are important diagnostic tools. In the presence of a visible cervical lesion, biopsy is the most important technique for confirming the clinical diagnosis.
Adenomyosis
Adenomyosis is the benign invasion of endometrium into the myometrium. Microscopic examination of the uterus reveals endometrial glands and stroma deep within the endometrium surrounded by hypertrophic and hyperplastic myometrium. This histopathologic diagnosis is made on careful microscopic evaluation of uterine specimens in more than 60% of hysterectomy specimens.22 Clinically, two thirds of patients with adenomyosis will complain of menorrhagia and dysmenorrhea, and pelvic examination usually reveals a diffusely enlarged and tender uterus.
Diagnostic tests that are suggestive of adenomyosis include transvaginal ultrasonography and magnetic resonance imaging (MRI). The sensitivity for ultrasonography probably approaches 50%, and the sensitivity of MRI ranges from 80% to 100%.22,23 Hopefully, more effective diagnostic tests and treatment besides hysterectomy will be developed in the future.
ABNORMAL UTERINE BLEEDING UNRELATED TO UTERINE PATHOLOGY
Many women experience heavy or irregular menstrual bleeding that is not caused by an underlying anatomic abnormality of the uterus. Although anovulatory bleeding is one of the most common underlying causes, a number of other unrelated causes, such as exogenous hormones and bleeding disorders, must also be considered (Table 21-3).
Table 21-3 Causes of Abnormal Uterine Bleeding Unrelated to Uterine Pathology*
* Referred to as “dysfunctional uterine bleeding” in the past.
Exogenous Hormones
Hormone Contraceptives
Today, approximately 10 million women in the United States use some type of hormonal contraception, including combination oral contraceptives, progestin-only pills, depot medroxyprogesterone acetate injections, progestin-containing intrauterine devices, subdermal levonorgestrel implants, transdermal combination hormone patches, and intravaginal rings (see Chapter 26). In addition to being a common reason to visit primary care physicians, AUB is a major cause of contraception discontinuation and subsequent unplanned pregnancy.
If abnormal bleeding persists beyond 3 months, other common causes should be excluded. In young sexually active women, sexually transmitted diseases should be excluded; in one study, almost one third of women on oral contraceptives who experienced abnormal bleeding were found to have otherwise asymptomatic Chlamydia trachomatis infections.24 If no cause for AUB other than hormonal therapy is found, treatment options include the use of supplemental estrogen and changing to an oral contraceptive with a different formulation with a different progestin or higher estrogen content (see Chapter 26).
Hormone Replacement Therapy
Hormone replacement therapy (HRT) after the menopause is a common iatrogenic cause of AUB. Unopposed daily estrogen therapy is associated with the highest rates of irregular bleeding and subsequent discontinuation of therapy.25 The addition of sequential or continuous oral progestins is associated with decreased irregular bleeding and reduced rate of endometrial hyperplasia. Sequential progestins result in the lowest rate of irregular bleeding during the first year of therapy, but the rate for sequential and continuous therapy is similar thereafter.
Each selective estrogen receptor modulator (SERM) is associated with a distinctive risk of AUB, which varies according to their effect on the endometrium. Tamoxifen, the first SERM used clinically as adjuvant treatment for breast cancer, exhibits antiestrogenic activity in the breast but stimulates the endometrium.26 As a result, tamoxifen has an incidence of postmenopausal vaginal bleeding similar to unopposed estrogen and likewise increases the risk of endometrial pathology, including endometrial polyps, hyperplasia, and cancer.
Raloxifene, a SERM approved for the prevention of osteoporosis, has little if any estrogenic effect on the uterus, resulting in atrophic endometrium.27 As a result, the risk of vaginal bleeding for women taking raloxifene is not increased compared to women not taking any form of HRT.
Ovulation Defects
Abnormal or absent ovulation is one of the most common causes of AUB during the reproductive years. A brief description of normal menstrual physiology (which is covered in depth in Chapter 1) is helpful in understanding anovulation as an underlying cause of AUB.
Normal Menstruation
Withdrawal of progesterone and estrogen results in menstruation, which involves the breakdown and uniform shedding of much of the functional layer of the endometrium, which is enzymatically dissolved by matrix metalloproteinases.28 Normal menses occur every 28±7 days, with duration of flow of 4±2 days and a blood loss of 40±40mL.29 Hemostasis is achieved by a combination of normal coagulation mechanisms and vasoconstriction of the spiral arterioles.
